Mechanisms of Escape from TGF? Tumor Suppression in the Pancreas With a five-year survival rate of less than six percent, pancreatic ductal adenocarcinoma (PDAC) is projected to become the second most common cause of cancer deaths by 2030 in the United States-unless progress is made in preventing or treating it. Genetic and histologic evidence from human PDAC suggest that the transforming growth factor ? (TGF?) pathway is tumor suppressive in the early stages of PDAC development. The goal of this project is to better understand the conditions under which TGF? mediates tumor suppression in the pancreas and to identify targetable signaling pathways that cause failure of TGF? tumor suppression. We have delineated a mechanism by which TGF? induces conflicting differentiation programs in premalignant pancreatic cells, resulting in apoptosis. This mechanism provides a selective pressure favoring the inactivation of the TGF? pathway, particularly via SMAD4 deletion and mutation. Half of PDACs retain a competent TGF? pathway, however, suggesting that there are additional ways for pancreatic cells to circumvent TGF?-mediated apoptosis. Our preliminary evidence suggests that up-regulation of AKT signaling is one way by which cells can bypass TGF?-mediated tumor suppression. In Aim 1, I plan to (a) use mouse models to explore the possibility of exploiting the interaction between AKT and TGF? signaling to inform treatment of TGF?-competent PDAC and (b) to define a mechanism for the crosstalk between the two pathways using gene expression profiling. In Aim 2, I seek to (a) use next generation sequencing of mouse models to identify additional pathways that allow cells to overcome TGF?-mediated tumor suppression and (b) functionally characterize the interaction of an identified pathway using an embryonic stem cell-based mouse model. Through these studies, I hope to provide insight into the interplay of the signaling networks that drive the progression of pancreatic cancer and generate a better understanding of targetable vulnerabilities in this cancer type.